In 1960, DeSanto rose to national prominence when her single "I Want to Know" reached number four on Billboard's Hot R&Bchart. She recorded the song with her husband Pee Wee Kingsley. Soon thereafter her marriage to Kingsley fell apart, and DeSanto moved to Chicago and signed with Chess Records in 1962 as a recording artist and writer. Among her recordings at Chess were "Slip-In Mules", "Use What You Got", "Soulful Dress" (her biggest hit at Chess), and "I Don't Wanna Fuss". DeSanto participated in the American Folk Blues Festival tour of Europe in 1964, and her lively performances, including wild dancing and standing back flips, were widely appreciated.

In 1965 DeSanto, under the name Peylia Parham, began a writing collaboration with Shena DeMell. They produced the song "Do I Make Myself Clear", which DeSanto sang as a duet with Etta James, which reached the top 10. It was followed up by a 1966 DeSanto-James duet, "In the Basement".[1] DeSanto's next song, "Go Go Power", did not chart, and DeSanto and Chess parted ways.

Sugar Pie DeSanto kept on writing songs and recorded for a few more labels without much success; she eventually moved back to the Bay Area, settling in Oakland.

Though it had often been said that her stage performances far surpassed her studio recordings, a full length live recording, Classic Sugar Pie, was not released until 1997.

DeSanto was given a Bay Area Music Award in 1999 for best female blues singer. In September 2008, she was given a Pioneer Award by the Rhythm and Blues Foundation. DeSanto received a lifetime achievement award from the Goldie Awards in November 2009.

DeSanto was married twice to Jesse Earl Davis, over the course of a 27-year relationship. In October 2006, he died attempting to extinguish a fire that destroyed their apartment in Oakland, California.[1]